The present invention concerns lipid-based compositions and use of such compositions in the treatment of withdrawal syndromes or cancer.
Withdrawal syndromes can occur during rehabilitation from addiction to drugs, alcohol, cigarettes and from an abrupt decline in the level of various hormones such as that occurring in menopause women. It is expressed in symptoms of seizures, sweat, tremor, nausea, depression, increase in rate of heart beat and in blood pressure, and others. Typically such addiction is treated by a xe2x80x9cwash outxe2x80x9d period in which the dependency is gradually removed with or without drug intervention. This process is painful and tedious and candidates are thus very often discouraged from entering it. There is thus a strong need for a solution that can ease the difficult period of withdrawal and that would allow people to return to normal life without much complications.
A basic biochemical phenomenon shared by most of the withdrawal syndromes is a change in the composition and in the structure of neuronal cell membranes which is expressed in membrane xe2x80x9cfluidityxe2x80x9d (Hannan, Am. Rev. Respir. Dis., 140 (1989), 1668-73; Crews, Psycho-pharmacology, 81 (1983), 208-13; Harris, Life Sci., 35 (1984), 2601-8; Heron et al., Eur. J. Pharmacol., 83 (1982), 253-261). These changes can at times be counteracted by administration of special natural preparations, resulting in the reduction of the symptoms related to the withdrawal processes (Heron et al., Eur. J. Pharmacol., 83 (1982) 253-261; Shinitzky, Physiology of membrane fluidity, (1984), Vol 1, Chapt. 1).
Multi-drug resistance (MDR) is also related to change in the fluidity of the cell membrane (Seydel et al. Arch. Pharm., 327, 601-610, 1994). MDR is a major cause of failure of cancer therapy involving use of cytotoxic drugs, particularly in recurring cancer.
Phosphatidic acid (PA) is a natural phospholipid found in plants and animal tissues. Its content usually does not exceed 5% of the total phospholipids in any of these sources. Therefore, lipid extracts available for human consumption (e.g., soybean phospholipids) are low in PA. Other sources of processed lipid mixtures for per os consumption or intravenous injection are devoid of PA. These include AL 721 (Antonian et al., Neurosci. Biobehav. Rev. 11 (1987), 399-413); Bros(trademark) (Fidia Sp. A. Abano-Terme, Italy) or Intralipid(trademark) (Vitrum Inc., Stockholm, Sweden).
Enzymatic procedures utilizing the enzyme phospholipase D for the hydrolysis of phospholipids to PA are known (Waite, M. Ed. The phospholipases, Plenum Press, N.Y., 1987). However, hitherto no use of such procedures to enrich natural lipase preparations with PA has been made. PA incorporated in a liposome containing phosphatidyl choline preparation was shown to reduce toxicity and enhance anti-fungal activity of the anti-fungal drug Hamycin. It was shown that PA had a strong protective effect and increased the survival of mice by 90% after seven days of therapy, as compared to mice treated with Hamycin alone (Moonis M. et al., J. Anti. Microb. Chemother., 31:569-579, 1993). Furthermore, a liposome preparation comprising PA was shown to counter symptoms of kidney toxicity caused by amino glucoside antibiotics as demonstrated by a recuperation in the kidneys"" phosphatase activity (Mingert-Leclercq. M.P., et al., Biochem. Pharmacol., 40:489-497, 1990).
The following is the meaning of some terms of which use will be made in the text below:
Withdrawal syndromexe2x80x94a syndrome which is a result of deprivation of the body of a substance to which the body was exposed continuously over a period of time. Such a substance may be an exogenous substance, taken by the individual or may be an endogenous one. Exogenous substances may include, for example, drugs of abuse, e.g. heroin, cocaine, morphine, and others; a variety of therapeutic drugs, e.g. sedatives; tobacco, alcohol, and others. Endogenous substances may include a variety of hormones, particularly such hormones the level of which changes at a certain age. Typical examples of withdrawal syndromes are such that occur in addicts during rehabilitation from addiction to drugs, alcohol, tobacco and other exogenous factors. Another example is that occurring in menopausal women, resulting from change in hormonal level during the menopause.
Withdrawal symptomsxe2x80x94symptoms appearing in an individual having a withdrawal syndrome. Examples are nausea, sweating, shaking, and substance craving, in drug of abuse associated withdrawal syndromes; hot flushes in menopausal women, etc.
PA-enriched lipid preparation (PA-E-LP)xe2x80x94a lipid preparation comprising at least 10% (w/w) of PA, preferably above about 10% and typically within the range of about 20%-75% of PA, out of the total lipid content of the composition.
Natural PA-E-LPxe2x80x94a PA-E-LP derived from it natural lipid preparation, e.g. a phospholipid preparation derived from plants, from animal tissue, or any combination thereof. Such a natural phospholipid preparation may typically be derived from soybean, from egg yolk or from animal sera. The natural PA-E-LP is prepared from a natural phospholipid preparation, typically by an enzymatic process. In a natural PA-E-LP, the remainder of the lipids consist primarily of phospholipids although small quantities, e.g. 0.1-10%, of other lipophilic substances, such as cholesterol, fatty acids, etc., may also be included in the preparation.
In accordance with the invention, a natural PA-E-LP was prepared by an enzymatic process. Such a natural PA-E-LP constitutes one aspect of the invention.
In accordance with the invention it was also discovered that PA-E-LP, and particularly natural PA-E-LP, is effective in the treatment of certain human conditions. It was furthermore surprisingly found in accordance with the invention, that PA-E-LP, and particularly natural PA-E-LP is effective in increasing the fluidity of cell membranes and countering various symptoms associated with or involving changes in membranes"" fluidity, such as withdrawal symptoms or treatment intended to sensitize MDR resistant cancer cells.
The present invention thus provides by one of its aspects a lipid preparation derived from a natural source enriched to comprise at least about 10% PA, preferably at least about 20% PA and most desirably above 50% PA. Typically, the concentration of PA as a total lipid ingredient, would not exceed 75%.
The concentration given above and below as xe2x80x9c%xe2x80x9d means to denote the number of weight units of an ingredient per 100 weight units of the entire composition (w/w).
The natural PA-E-LP is preferably obtained from a natural phospholipid preparation by enzymatic treatment using, a synthetic or natural source comprising the enzyme phospholipase-D. The natural phospholipid preparation may be of vegetable origin, may be of animal origin, or a combination thereof. Typical examples of natural phospholipid preparations useful for the preparation of natural PA-E-LP of the invention are, soya lecithin, egg yolk and phospholipids from animal serum. Examples of phospholipase-D sources, are peanuts, typically ground peanuts or a phospholipase-D fraction derived therefrom. Phospholipase-D or a phospholipase-D source is added in an amount and for a time sufficient to hydrolyze at least about 10% or preferably about 25% and most preferably about 50% of the phospholipids to yield PA-E-LP.
By another aspect of the present invention there are provided pharmaceutical compositions comprising PA-E-LP as the active ingredient. Particularly preferred are such compositions comprising natural PA-E-LP as the active ingredient. Examples are pharmaceutical compositions for use in reducing withdrawal symptoms; pharmaceutical compositions for use within the framework of cancer treatment to increase sensitivity of cancer cells, particularly such cells possessing MDR properties, to cytotoxic drugs; etc.
Also provided in accordance with the invention is a method for the treatment of a human condition or disease comprising administering to a patient in need, an effective amount of PA-E-LP.
The term xe2x80x9ceffective amountxe2x80x9d should be understood as in amount of an ingredient sufficient to yield a desired therapeutic effect. For example, within the framework of the treatment of withdrawal syndromes, an effective amount will be an amount which gives rise to permanent or temporary alleviation of withdrawal symptoms in individual, alleviation being either reduction of intensity of withdrawal symptoms or reduction in the rate of appearance of such symptoms, or generally improvement in any parameter characteristic of such withdrawal symptoms. In the case of anti-cancer treatment, an effective amount is an amount giving rise to increased sensitivity of the tumor cells toward cytotoxic drugs, as determined for example by a decrease in the size of a tumor mass.
The pharmaceutical composition of the invention may typically be orally administered although it may also be formulated for topical or parenteral administration. For oral administration the composition may comprise various flavoring agents, edible colors, etc. Furthermore the composition for oral use may also be encapsulated, e.g. in an enterocoated gelatine capsule.
For parenteral administration the composition will typically be injected intravenously (I.V.). Such a parenteral composition may for example comprise soybean multi-triglycerides, egg phospholipids, PA prepared in accordance with the invention, glycerol and distilled water.
A topical composition may be in the form of a gel or a salve and may thus comprise various additives known per se to allow the compositions to obtain such a physical form (e.g. a gelating agent).
The compositions may be used for the treatment of a variety of human conditions and diseases. One preferred embodiment of the invention is concerned with the treatment of withdrawal syndromes. The treatment may be manifested by a permanent improvement in an individual""s condition, e.g. the disappearance or reduction of intensity of the withdrawal symptoms, or a temporary disappearance or reduction of such symptoms during an attack.
Withdrawal syndromes which can he treated in accordance with the invention include treatment of menopausal women, particularly treating such women to reduce the occurrence of hot-flushes during the menopausal period; treatment of withdrawal syndrome during rehabilitation from smoking or drug or alcohol addiction; etc.
Another preferred embodiment of the invention is concerned with the treatment of cancer, particularly such related with acquired multi-drug resistance MDR. Development of MDR is a reaction of tumor cells to continuous exposure to cytotoxic agents both in vitro and in vivo. This mechanism is believed to be responsible for the resistance developed by cancer patients to chemotherapy treatment which is currently one of the most serious problems in cancer treatment. It has been shown that the sensitivity of tumor cells to various cytotoxic drugs is correlated with their potency for membrane fluidization. Treatment with the composition of the invention may increase the fluidity of the membrane of tumor cells present in an individual, thereby reversing their acquired multi-drug resistance to various cytotoxic drugs and thus enabling continuation of a chemotherapy regimen, which may result in the improvement of the treated individual""s condition.
The invention will now be illustrated in the following examples with occasional reference to the annexed drawings.